There has been a dramatic change in our concepts about the cortical control of movement. In the past, the primary motor cortex (M1) was viewed as the sole source of descending command signals to the spinal cord. Other cortical areas and subcortical structures like the basal ganglia and cerebellum were thought to influence the control of movement mainly through their connections with M1. We now know that the frontal lobe contains 6 premotor areas. Each of these cortical areas projects not only to M1, but also directly to the spinal cord. As a consequence, the central commands for movement may originate not only from M1, but also from each of the premotor areas. In this application, we propose to examine 2 fundamental questions about the organization of M1 and the premotor areas: 1) How are the cortical neurons that influence individual muscles in the hand, arm and shoulder distributed in the cortical motor areas? 2) What is the organization of the circuits that link the basal ganglia and cerebellum with the cortical motor areas? These questions will be answered in 3 experiments that will use transneuronal transport of neurotropic viruses. Virus tracing is a unique anatomical method that enables us to define circuits of synaptically linked neurons. In 1 experiment, we will inject rabies virus into single muscles and use retrograde transneuronal transport of the virus to label second-order neurons in the cerebral cortex that make monosynaptic connections with the motoneurons of the injected muscle. In a second experiment, we will inject rabies virus into physiologically defined regions of proximal or distal arm representation in the cortical motor areas and use retrograde transneuronal transport of the virus to label second-order neurons in the basal ganglia and cerebellum that project to the injection site. In a third experiment, we will inject the H129 strain of herpes simplex virus type 1 into the output nuclei of the basal ganglia or the cerebellum and use anterograde transneuronal transport of the virus to label third-order neurons in the cortical motor areas that are the target of the injection site. The results from these experiments are likely to have broad implications for concepts about the function of the cortical motor areas in normal movement, their role in the recovery of motor function following stroke and their involvement in the generation of abnormal movements like those associated with Parkinson disease. [unreadable] [unreadable] [unreadable]